Alcohol abuse and alcoholism are serious societal problems. Genetics play a major role in determining the risk for developing alcohol abuse disorders. Inbred and transgenic mice are powerful tools for examining the genetic and molecular basis of the effects of alcohol. Some transgenic and inbred mice have altered responses to the physiological and reinforcing effects of ethanol. It has not been determined if the subjective discriminative effects of ethanol are different across strains of inbred mice or altered in transgenic mice. We propose to examine the discriminative stimulus properties of ethanol in two inbred mouse strains (C57BL/6 and DBA/2J) and one transgenic mouse line which over-expresses 5-HT3 receptors. The C57BL/6 mouse strain is characterized by high levels of ethanol drinking and decreased sensitivity to ethanol. The DBA/2J and 5-HT3 over-expressing strains drink less ethanol than controls and have increased responses to the motor activating effects of low dose ethanol. The first specific aim of this proposal is to train an ethanol discrimination in 5-HT3 over- expressers, B6SJL control mice, C57BL/6 mice and DBA/2J mice. It is hypothesized that all four strains will be capable of discriminating ethanol from vehicle but will differ in sensitivity to ethanol's discriminative stimulus effects. The second specific aim is to determine if test drug substitution patterns for ethanol systematically differ between transgenic and inbred mouse strains. It is hypothesized that genetic alterations of the 5-HT3 receptor system will effect not only the ability of 5-HT3 ligands to substitute for ethanol, but also drugs which act via the GABAA and NMDA receptor systems. It is also hypothesized that C57BL/6 and DBA/2J mice will differ from one another in the substitution patterns of the test drugs for ethanol. These studies will characterize the discriminative stimulus effects of ethanol in transgenic and inbred strains of mice. These experiments will also explore the direct consequences of alterations of the 5-HT3 receptor systems to the discriminative stimulus effects of ethanol anal the contribution of genetic. background to the ethanol's discriminative ctimnlnc effects.